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In molecular transition metal catalyst architectures, ligand design plays a crucial role in enhancing the efficiency of catalytic reactions. Selected ligands can play a bifunctional role in ligand-assisted catalysis, providing first coordination sphere basic sites and facilitating formation of multinuclear species through monomer bridging, as well as through their electronic and steric effects. This research addresses the underutilization of SNS complexes in various catalytic cycles. Our aim is to expand their activity in different cycles, unlocking untapped reactivity. Specifically, we focus on SNS ligands with soft thiolate and hard amido donors, comparing their catalytic performance in diverse coupling reactions. This comparative study provides insights into the suitability of these ligands with different transition metals, contributing to the understanding of ligand-assisted catalysis. Chapter 1 introduces these concepts and outlines the relevant catalytic reactions studied herein. To gain a deeper understanding of the chemistry involved, a comparative analysis of the reactivity differences between transition metal complexes with similar coordination structures is conducted. This investigation is crucial as it provides valuable insights into the design of suitable ligands for transition metal catalysts. Specifically, Chapters 2 and 3 of this thesis delve into a comparison of the reactivity of coordination complexes with identical metal centers and similar ligands, or even the same molecular formula, in catalysis. In the second chapter, we introduce a new cobalt (II) complex bearing an (SNS) amido ligand for the bifunctional hydroboration of carbonyls. Following an unsuccessful attempt to mono-protonate the amido donor in the bis(amido) complex Co(SᴹᵉNSᴹᵉ)₂ (2.1) treatment with 1 equivalent of 1,3-bis(1-adamantyl)imidazolium chloride (IAd•HCl) resulted in the liberation of one protonated ligand, affording CoᴵᴵCl(SᴹᵉNSᴹᵉ)(a-IAd) (2.2) with an "abnormally" coordinated IAd ligand, i.e., specifically bound through C4 instead of C2 of the imidazole ring. Compound 2.2 exhibited excellent catalytic activity in the hydroboration of aldehydes, displaying high substrate tolerance under mild reaction conditions and short reaction times. Stoichiometric reactions of 2.2 with pinacolborane (HBpin) revealed a bifunctional catalyst activation step, generating free SNS-amine, ClBpin and the active cobalt dihydride catalyst. Generation of an analogous catalyst with a normally coordinated IAd ligand showed poor reactivity in the hydroboration of aldehydes and was unable to effect ketone hydroboration. In Chapter 3, two tetranuclear copper(I) complexes bearing thiolate [Cu(SNSᴹᵉ)]₄ (3.1) and amido [Cu(SNSᴹᵉ)]₄ (3.2) SNS ligands are synthesized and their catalytic activity in a base-free azide-alkyne cycloaddition is compared. Complex 3.1 (1 mol%) demonstrated excellent reactivity for performing this 'click' reaction in water, exhibiting a broad substrate scope and enabling the production of various triazole compounds, including bioactive compound 3.16, which holds potential as an anti-cancer drug. DFT calculations suggested a proton shuttle role for the thiolate donor in conversion of the Cu-coordinated terminal alkyne to the key Cu-alkynyl intermediate. On the other hand, complex 3.2 exhibited reactivity similar to copper chloride. This observation was attributed to the basic nature of the amido ligand, which undergoes protonation by the coordinated alkyne C-H bond, with subsequent dissociation of the SNS-amine from the copper. Without a ligand to stabilize the copper in the less stable +1 oxidation state, a disproportionation reaction occurs, leading to catalyst deactivation. Chapter 4 introduces two palladium(II) thiolate complexes: PdI(κ³-SNSᴹᵉ) (4.1) exhibits catalytic activity in promoting the Heck cross-coupling reaction, while Pd(κ²-SNSᴹᵉ)₂ (4.2) affords no coupling product. In concert with triethylamine base, catalyst 4.1 efficiently produces olefin products with excellent yields, even at low catalyst loadings, and exhibits broad substrate tolerance over a 5 h reaction period. In contrast, the limited catalytic activity of 4.2 can be rationalized by proposing the formation of a Pd(N₂S₂) complex through ligand imine coupling at elevated temperatures, a reaction reported previously for Ni and Co analogs. The tetra-coordinated ligand formed through this isomerization occupies critical coordination sites around the metal, thereby preventing oxidative addition of the organohalide substrate, a key step in the Heck reaction mechanism. This work sheds light on the divergent catalytic behaviors of these two intriguing complexes. Finally, in Chapter 5 we assess what has been learned and identify relevant implications for further work.

<p dir="ltr">LeadGlow (<b>LG</b>) was reported in 2009 for its ability to both sensitively and selectively detect Pb²⁺ in aqueous solutions. Utilizing the synthetic approach of <b>LG</b>, it is possible to generate a class of novel fluorophores. A derivative of first-generation <b>LG </b>was synthesized and reported here for the first time, intuitively named <b>LG2</b>. Both compounds contain interesting photophysical properties that have not been extensively researched prior to this work. Because of this, photophysical properties of both <b>LG</b> and <b>LG2</b> are unveiled here for the first time. These properties were investigated by determinations of quantum yield (QY), average fluorescence lifetime, and DFT calculations. <b>LG</b> was found to have a higher QY (0.057) than <b>LG2</b> (0.011); however, <b>LG2</b> displays an average fluorescence lifetime (3.186 ns) 5x greater than that of <b>LG</b>. Both <b>LG </b>and <b>LG2</b> are synthesized via Hg²⁺-facilitated desulfurization of their respective thiocarbonyls, resulting in a turn-on fluorescence feature. The thiocarbonyl-containing fluorophores (<b>SLG </b>and <b>SLG2</b>) display quenched fluorescence compared to their oxo-derivatives (<b>LG </b>and <b>LG2</b>), this work attempts to investigate the mechanism(s) responsible.<b> </b>A whole class of LeadGlow compounds can be synthesized and could be potentially used as fluorescence-based sensors.</p>

<p dir="ltr">Post-translational modification (PTM) is an important biological process by which cells regulate their signaling pathways. De-regulation of these signaling pathways often leads to many diseases. Protein AMPylation is a recently discovered PTM that caught a great amount of attention for its involvement in neurodevelopment and neurodegeneration. However, the mechanisms by which protein AMPylation modulates these biological processes remain mostly unknown. FIC domain protein adenylyltransferase (FICD)<b> </b>is one of the only two known AMPylators in eukaryotes, and its physiological role remains largely unexplored. By using a chemical approach, we identified two direct substrates of FICD: Peroxiredoxin 1 (PRX1) and Peroxiredoxin 2 (PRX2). These are antioxidant enzymes responsible for protecting cells from oxidative stress, which has been implicated in many neurodegenerative diseases. In addition, we found that FICD-mediated AMPylation increased PRX1 and PRX2 enzymatic activity <i>in vitro</i> and their protein levels in cells. These findings established a link between FICD-mediated AMPylation and oxidative stress, suggesting a potential neuroprotective role of FICD in neurodegenerative diseases.</p><p dir="ltr">Protein phosphorylation is another PTM that has been under extensive study due to its widespread role in cell signaling in many biological processes such as growth, division, metabolism, membrane transport, etc... Deregulation of protein kinases, which catalyze phosphorylation reaction, is often implicated in many diseases, including cancer. To elucidate disease mechanisms and explore alternative therapeutic targets, identifying direct protein substrates of a given disease-relevant kinase is crucial but remains a major challenge. Conventional methods to study phosphorylation involved the use of radiolabeled ATP, which poses health hazards and lacks reliability due to rapid decay of radioactive isotope. In this research, we developed an alternative method with a series of novel γ-modified ATP analog probes bearing a phospho-alkyne reporter handle, and their effectiveness and efficiency for<i> </i><i>in vitro</i> phosphorylation of recombinant proteins and proteomic substrate labeling in cell lysate were examined.</p>

Iminosugars are carbohydrate mimics, where the endocyclic ring oxygen has been replaced by nitrogen. This substitution affords these compounds their inhibitory activity towards sugar-processing enzymes (glycosidases) and, as a consequence, their chemotherapeutic potential in the treatment of a broad range of diseases. Several iminosugars are currently in clinical trials or have entered the market as approved drugs. This has consequently led to increasing levels of research into their synthesis and application, both in terms of the development of efficient methodology to access naturally occurring examples, and also to elaborate novel scaffolds. The presence of multiple chiral centres within iminosugars provides a considerable challenge in accessing these targets by asymmetric means, whereas carbohydrates pose a more attractive chiral pool. As such the majority of literature methods have employed this latter method. The focus of the thesis is on the elaboration of robust methodologies to access both naturally occurring and novel iminosugars, and their precursors, from readily available carbohydrate starting materials. Chapter 1 presents an introduction to iminosugars, including an overview of glycosidase inhibition by this class of sugar-mimic, their historical medical usage and the basis for their potential employment in treating diabetes, lysosomal storage disorders (LSDs) and cancer. This chapter also gives a general review of the methods employed in the literature for the assembly of iminosugar scaffolds. Chapter 2 is concerned with the synthesis of iminosugars from the carbohydrate glucuronolactone. This versatile chiron has previously allowed for access to many homochiral targets, and in this thesis is used to access DGJNAc on a gram-scale. This iminosugar has been shown to be a potent α-N-acetylgalactosaminidase inhibitor and is potentially extremely valuable in the treatment of late-stage cancer. Both enantiomers of glucuronolactone are also utilised in the divergent synthesis of every stereoisomer of two classes of five-membered iminosugars; the pyrrolidines (including DMDP), and the proline amides. These compounds demonstrate remarkable biological activity against a panel of glycosidases and hexosaminidases, allowing for the analysis of the structure-activity relationship between these compounds and the target enzymes. Chapter 3 describes the development of a novel, one-pot methodology - a tandem Strecker reaction and iminocyclisation - for the assembly of trihydroxy piperidine α-iminonitriles from a range of unbranched and branched pentose monosaccharides. These piperidine α-iminonitriles are precursors to pipecolic acids which may also be potentially valuable targets in the treatment of cancer.

This work describes developments in new azetidine and azetine chemistry; specifically, methods developed for the introduction of functionality α- to nitrogen in both ring systems, with additionally in situ formation of the latter system, from azetidine substrates. Chapter 1 discusses the growing importance of azetidines, and the current methods available for making substituted azetidines by ring formation. Further discussion comprises of current sp³ C–H activation approaches α- to nitrogen in heterocyclic compounds as potential methods for sp³ C–H activation on azetidines to give substituted azetidines. Previous work by the Hodgson group in this area is detailed. Chapter 2 describes the advance made towards 2,3-disubstituted azetidines using the thiopivaloyl protecting/activating group, where the latter plays a key role. Optimisation, scope, selectivity and mechanistic insight into the α-deprotonation–electrophile trapping of a 3-hydroxy azetidine system is discussed, which successfully gives access to a range of 3-hydroxy-2-substituted azetidines. Preliminary investigations with 3-alkyl-2-substituted azetidines are also described. Chapter 3 describes the development of a straightforward protocol to make 2-substituted-2- azetines, a rarely studied and difficult to access 4-membered azacycle subclass, from readily accessible azetidine starting materials using α-deprotonation–in situ elimination followed by further α-lithiation–electrophile trapping. Extension of this methodology by transmetallation from the intermediate organolithium to the organocuprate, resulting in greater electrophile scope, is also described.

Well-regulated Ca2+ signalling is essential for every living organism, and disruption of this signalling can lead to diseases including heart failure, neurological disorders and diabetes. Intracellular Ca2+ levels are regulated by influx of extracellular Ca2+ through channels located in the cell membrane. In addition, release of Ca2+ from intracellular stores also plays an important role in controlling intracellular Ca2+ concentration. Of the three types of intracellular Ca2+ stores that have been characterised those with D-myo-Inositol 1,4,5 trisphosphate receptors (InsP3Rs) showed a close relationship with cell proliferation. Hence, selective blockage of InsP3Rs will allow better understanding of Ca2+ signalling and might also unveil novel treatment for cancers, in the long term. There were no selective InsP3Rs antagonists known at the start of these studies. Based on the crystal structure of InsP3Rs bound to InsP3 and SAR studies of InsP3, we designed and tested several InsP3 analogues.1 Compound 15, 16 and 23 acted as InsP3R antagonists, though their selectivity for InsP3Rs was not completely determined. Furthermore, we also attempted to improve the potency of 16 via substitution at the 1-postion phosphate. By considering the interaction formed between adenophosphostins and InsP3Rs compounds (53-55) were designed and synthesised. In addition, analogues of compound 92, selected from an in silico screen, have led to the discovery of another novel scaffold that acts as an InsP3R antagonist.

Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular S_N2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.

Systemic administration of adenovirus type 5 (Ad5) vectors for the treatment of cancer is limited by poor circulation kinetics and inefficient uptake from the bloodstream into tumours. This study reports a novel method for linkage of highly-PEGylated gold nanoparticles (AuPEG) to Ad5 by a single reduction cleavable bond. The resulting ‘dandelion’ structure provides very effective steric shielding with only minimal and reversible modification of the Ad5 capsid. This ablates in vitro cell infection, improves protection against the binding of antibodies, and enhances in vivo circulation kinetics. Focused ultrasound is a promising technology for the non-invasive, targeted treatment of cancer. In the context of drug delivery, cavitational energy generated upon exposure of ultrasound contrast agents to focused ultrasound can be used as a powerful stimulus to move therapeutics over distances of hundreds of microns away from blood vessels. In addition to providing a platform for effective stealthing, conjugation of AuPEG to Ad5 also increases the effective density of Ad5. This increase in density imparts a second major advantage on the strategy, observed for the first time in the present study: denser particles are transported significantly farther by cavitation-induced microstreaming than identically-sized particles of lower density. Specifically, in in vitro tests using a tumour-mimicking flow-channel phantom model and in in vivo experiments using tumour bearing mice, Ad5–AuPEG was delivered farther from vessels in response to ultrasound induced cavitation than either naked Ad5 or polymer-coated Ad5. The enhancements in stealthing and improvements in response to ultrasound provided by this strategy enabled up to 12% (S.D. 0.97) of the injected dose to be deposited in the tumour, compared to just 0.12% (S.D. 0.05) for Ad5 without ultrasound (p < 0.001). Consequently, in a survival study, mice treated with Ad5–AuPEG with focussed ultrasound had the slowest tumour growth and longest survival rate when compared to mice treated with Ad5 alone, Ad5–AuPEG alone, or Ad5 with focussed ultrasound. These results provide compelling evidence that the combination of focussed ultrasound with density-augmented stealthed Ad5 results in improved delivery to tumours and therapeutic efficacy. This combination of ultrasound with particle modification for optimal cavitation-mediated delivery has the potential to be applied to a broad range of anti-cancer nano-medicines and therapeutics to augment their bio-availability for improved cancer treatment.

Manganese(III) acetate mediated radical cyclisations provide a mild and powerful tool in the construction of complex bicyclic systems. This thesis focuses on the formation of a number of alkenyl substituted [3.3.0]-bicyclic γ-lactones utilising a manganese(III) acetate/copper(II) triflate induced radical cyclisation. The methodology was then applied to a short catalytic and enantioselective synthesis of (+)-aphanamol I and related natural products. Chapter 1 presents a summary of the theories and methodology which will be utilised in this work. In particular, a key focus will revolve around oxidative radical cyclisations and how manganese(III) acetate has become a vital oxidant in such areas. Chapter 2 details a catalytic and asymmetric total synthesis of (+)-aphanamol I. Following an overview of the natural product and its previous total synthesis, a racemic and asymmetric total synthesis is presented which utilises a manganese(III) acetate mediated radical cyclisation and a Claisen ring expansion as key steps. Chapter 3 reports the synthesis and subsequent cyclisation of a wide range of dienyl malonate substrates. Variation of the γ-substituent is first explored, demonstrating the effect that substituent size has on the diastereoselectivity of the cyclisation. Following this, the synthesis of [2.3.0]-,[4.3.0]- and [5.3.0]- bicyclic γ-lactones are investigated. Chapter 4 describes studies towards the total synthesis of a dolabellane natural product. Investigations into substrate synthesis which can be used in a RCM will be presented. Full experimental details and spectral data, with select NMR spectra are also provided.